Gamma-keto-tertiary amines and derivatives thereof



United States GAMMA-KETO-TERTKARY AMINES AND DERIVATIVES THEREOF GwyneddValley, and Everett M. Pa., assignors to Merck & C0., N. J., acorporation of New Jersey No Drawing. Application July 14, 1953 SerialNo. 367,988

6 Claims. (Cl. 260-2947) James M. Sprague,

Schultz, Ambler, Ind, Railway,

the non-toxic acid salts and the quaternary ammonium derivativesthereof, in which A, is an aryl radical selected from the unsubstitutedphenyl radical and a phenyl radical containing not more than 2substituents selected from the group consisting of hydroxy, lower alkyl,chlorine, bromine and lower alkoxy radicals; R is chosen from the groupconsisting of a lower alkyl, cycloalkyl, allyl, A and A =CH R is chosenfrom the group consisting of hydrogen, hydroxy, lower alkyl, allyl,cycloalkyl, A,- and A,.-CH and NX is chosen from the class consisting ofdi-lower alkylamino, l-piperidyl, and 4-morpholinyl.

The gamma-keto-tertiary amines of this invention are obtained by thereaction of ketones of the general formula with formaldehyde and asecondary amine, I-INX, according to the Mannich reaction:

The particular adaptation of the Mannich reaction used in this inventionconsists in admixing the appropriate ketone with the hydrochloride ofthe proper secondary amine and paraformaldehyde with or without anappropriate solvent in a reaction vessel equipped for refiux. Tothis-mixture is added a small quantity of alcoholic hydrochloric acid.This mixture is stirred mechanically and maintained at a temperature ofapproximately 100 C. until the mixture becomes homogeneous.

The refiux apparatus is then removed and the heating continued untilformaldehyde is no longer evolved. On cooling, the reaction mixturecrystallizes and the product, the hydrochloride of the aminoketone, ispurified by recrystallization.

The quaternary ammonium derivatives are prepared by reacting the freeaminoketone base with quaternizing agents according to known procedures.The usual quaternizing agents can be employed for this purpose, for

, atefit.

III

It is more particularly concerned with example, dialkylsulfates asdimethylsulfate, diethylsulfate and the like, alkyl halides as methylchloride, ethyl bromide and the like, arylaliphatic halides as benzylchloride, cinnamyl iodide and the like which illustrate a fewrepresentative types.

The gamma-keto-tertiary amines and their quaternary ammonium derivativesof this invention are useful for their anticholinergic properties.

The invention is illustrated by, but not restricted to, the followingexamples:

Example 1 1-phenyl-1-elthyl-4-zllmethylaminO Z-bumnone hydrochloride.3-phenyl 2 pentanone (16.2 grams, 0.1 mole), paraformaldehyde (4.5grams, 0.15 mole), dimethylamine hydrochloride (12.2 grams, 0.15 mole),and 10 drops of 8 N alcoholic hydrogen chloride were mixed and heatedwith shaking on a steam bath. First, two layers formed, but afterheating for five hours there was obtained a homogeneous yellow oil thatsolidified to an oily solid on cooling. The solid was triturated withabsolute ether, collected by filtration, and dissolved in water. Thecloudy solution was extracted with ether and made basic withconcentrated ammonium hydroxide solution. The free base was extractedwith ether. After washing the ether solution with water it was driedoversodium sulfate and concentrated by evaporation to a small volume toremove any dimethylamine. Then ether was added to make up the originalvolume and the base was precipitated by the addition of hydrogenchloride. The white solid, l-phenyl-1-ethyl-4-di.methylamino-2-butanonehydrochloride, was collected by filtration, washed with ether, dried invacuum over sulfuric acid and crystallized from reagent acetone (300ml.). There was obtained 7.4 grams (30%) of product, M. P. 144-145.

Example 2 1 phenyl 1-ethyl-4-(J-piperidyl) -2-butonone hydrochloride. 3phenyl Z-pentanone 16.2 grams, 0.1 mole), paraformaldehyde (3.3 grams,0.11 mole), piperidine hydrochloride (12.2 grams, 0.1 mole), and 10drops of 8 N alcoholic hydrogen chloride were mixed in a round-bottomedflask fitted with a short air condenser and mechanical stirrer. Theflask was heated with stirring on a steam bath. After one hour thecontents became solid. The solid was triturated in ether and aftercollecting it by filtration it was crystallized three times from reagentacetone. There was obtained 5.3 grams (18%) of a white powder,1-phenyl-1-ethyl-4-(1- piperidyl)-2-butanone hydrochloride, M. P.162163.

Example 3 1-phenyl-1-n-propyl-4-(4-morpholinyl)- 2 butane/1ehydrochloride. 3 phenyl 2 hexanone (14.0 grams), morpholinehydrochloride (12.4 grams), paraformaldehyde (3.0 grams) and 1 ml. of 4N alcoholic hydrogen chloride were stirred and heated on a steam bathfor two hours. The solid cake that resulted was dissolved in 15 ml. hotisopropyl alcohol. A crystalline product separated when the solution waschilled. Upon recrystallization from a mixture of 10 parts of acetoneand 1 part of ethanol there was obtained 1- phenyl 1propyl-4-(4-morpholinyl)-2-butanone hydrochloride, M. P. 155.5156.5 C.

Example 4-1-phenyl-1-is0pr0pyl-4-(1-piperidyl)-2-bu tzmonehydrochloride. 4-methyl-3phenyI-Z-pentanone (257 grams, 1.46 mole),piperidine hydrochloride (199 grams, 1.63 mole) paraformaldehyde (46.4-grams, 1.55 mole) and 10 ml. 3 N alcoholic hydrogen chloride werestirred on a steam bath until the mixture solidified. This occurred inapproximately thirty-five minutes after which the solid cake was heatedfor an additional one-half hour. The cake was broken up and dissolved inboiling isopropyl alcohol (750 ml.), and the solution allowed to cool toroom temperature and then was chilled to 0 C. for approximately fourhours. The solid was collected on a filter and washed with one ml,portion of other after l 3 which it was dried and recrystallized fromboiling isopropyl alcohol. There was obtainedl-phenyl-l-isopropyl-4-(l-piperidyl)-2-butanone hydrochloride, M. P.183- 184 C.

Example 5-] pltenyl 1-is0propyl-4-dimethylumino- 2-bmanonehydrochloride-l isopropyl-l-phenylacetone (35.3 grams, 0.2 mole),paratormaldehyde (16.6 grams, 0.22 mole), dimethylamine hydrochloride(17.9 grams,

0.22 mole), and 2 ml. of 9% alcoholic hydrogen chloride were reactedaccording to the procedure described in Example 3. The mixture washeated for twenty three hours, the last 16 hours without stirring, andthe solid product was triturated with ether and recrystallized fromtertiary butyl alcohol. There was obtained 28 grams (52%) of whitecrystalline solid, 1-phenyl-1-isopropyl-4-dimethylamino-Z-butanonehydrochloride, M. P. 163-164".

Example 6-N-(3-0x0--4 phenyl 5 methyIhexyl)-trimethylammoniummetlzylsulfate.5.4 grams (0.02 mole) ofl-phenyl-l-isopropyl-4-dimethylamino-2-butanone hydrochloride, obtainedas described above in Example 5, was dissolved in water and the solutionmade basic by addition of aqueous sodium hydroxide. The insoluble basethus obtained was separated by filtration and then taken up in ether andthe ether solution dried over potassium carbonate. Dimethylsulfate wasadded gradually to the ethereal solution of the base. A vigorousreaction ensued and a precipitate appeared immediately. After thereaction mixture had been kept at 20-25 C. for one hour, the solidprecipitate was collected by filtration. It weighed 6.5 grams, M. P.140-144 C. After two crystallizations from isopropyl alcohol, there wasobtained 5.4 grams (76% yield) of N43-oxo-4-phenyl-5-methyl)-hexyl-trimethylammonium methylsulfate, M. P. 146

Example 7] phenyl-l-allyl-4-dimethylamino-Z-bura none hydr0chl0ria'e.-Amixture of 1-al1yl-1-phenylacetone (17.4 grams, 0.1 mole),paraformaldehyde (3.3 grams, 0.11 mole), dimethylamine hydrochloride(8.2 grams, 0.11 mole) and 1 ml. alcoholic hydrogen chloride was stirredand heated for one and three-quarter hours in a manner similar to thatdescribed in Example 3. After cooling and triturating the reactionproduct with ether the insoluble residue was boiled with 300 ml. of drybenzene. The hot benzene solution was decanted through a filter from alayer of undissolved oil. On cooling the benzene deposited 3.6 grams ofa white powder. The oil from the benzene extraction was dissolved in hotacetone. On cooling, this solution deposited 2.8 grams of material. Thetwo solid materials were combined and recrystallized from acetone togive 5.5 grams (20%) of white powder,l-phenyl-l-allyl-4-dirnethylamino-2 butanone hydrochloride, M. P.125-127".

Example 81 -phenyl-1 -la11ryl-4 -aimethylamirto-Z-butanonehydrochloride.3 phenyl 2 pentadecanone (13.2 grams, 0.1 mole),paraformaldehyde (3.3 grams, 0.11. mole), dimethylamine hydrochloride(8.2 grams, 0.1 mole), and drops of 8 N alcoholic hydrogen chloride weremixed in a round-bottomed flask fitted with a short air condenser and amechanical stirrer. The flask was heated with stirring on a steam bathand after the contents became solid. the solid was triturated in ether.After collecting it by filtration, it was recrystallized from reagentacetone yielding the desired product, 1-phenyl-1-lauryl-4-dimethylamino-Z-butanone hydrochloride.

Example 9-1 plzenyl-J-benzyl-4-dimethylamin0-2-batanonelrydr0chl0ride.Paraformaldehyde (3.3 grams, 0.11 mole), dimethylarninehydrochloride (8.2 grams, 0.1 mole), 3,4-diphenyl-2-butanone (19.5grams, 0.1 mole) and 10 drops of alcoholic hydrogen chloride were heatedon a steam bath with occasional shaking for seven hours. A homogeneousyellow oil resulted. This became semisolid on standing for 16 hours andwas first triturated in 10 milliliters of hot dry benzene and thentriturated with 10 ml. of cold reagent acetone. The residue wascrystallized from 100 ml. of acetone to give 9.05 grams of fine whitepowdery solid, lphenyl-l"bcnzyl-4-dirnethylamino- Z-butanonehydrochloride, M. P. 129-l30 C. Chilling the filtrate in the icebox gavean additional 1.98 grams of pure product, M. i. 129l30 C. for a totalyield of 11.03 grams (34.7%).

Example 10-1-pl1enyl-1-benzyl-4-(I-pipericlyl)-2-butanonehydroclrl0ride.-A mixture of 3,4-diphenyl-2-butanone (22.4 grams, 0.10mole), paraformaldehyde (4.5 grams, 0.15 mole), pipcridine hydrochloride(12.2 grams. 0.10 mole), and 1 ml. of 3 N alcoholic hydrogen chloridewas with stirring on a steam bath for 20 minutes. At this point thecontents of the flask solidified. The reaction mixture was dissolved inwater and the solution extracted with ether. The aqueous layer was madebasic with 20% sodium hydroxide and the free base was extreated withether. fter the ether solution had been washed with water untilpractically neutral, it was dried yer sodium sulfate and the solvent wasevaporated under reduced pressure at 30 C. to remove any unreactedpiperidine. The residue was then taken up in absolute ether. Then dryhydrogen chloride was added to precipitate the aminoketone as thehydrochloride. The crude dried product weigh-ed 24 grams. Twocrystallizations from acetone were required to obtain the pure product,l-phenyl-lbenzyl-4-(1-piperidyl)-2-butanone hydrochloride, M. P. -148 C.(16 grams, 47% yield).

Example 11-] -plrenyi-1 onelhyl -l1 ycli'oxy-4-d imethylamin0-2butait0ne hydroclzl0ride.3-hydroxy-3-phenyl-2- butanone (16.4grams, 0.10 mole), paraformaldehyde (4.5 grams, 0.15 mole),dimethylamirre hydrochloride (8.15 grams, 0.1 mole) and 1 ml. of 3 N acoholic hydrogen chloride were heated on a steam bath with stirring forfour hours under an air condenser and for an additional hour in the openflask. The resulting clear oil solidified after standing at roomtemperature for a few hours. The solid mass was triturated with etherand after collecting by suction filtration the precipitatewascrystallized four times from acetone. There was obtained 4.85 grams(19% yield) of l-phenyl-1-methyl-1-hydroxy--4-dimethylarnino-2-butanonehydrochloride, M. P. 112l14 C.

Example 12-] -plze!1yl- I methyl 1 ltydl0xy-4-(J- piperr'dyl)-2-butmt0nehydrochloride. By substituting in Example 10 an equimclar quantity ofpiperidine hydrochloride for the dimethylamine hydrochloride there used,and following the procedure as outlined, there was obtained 15.7 grams(66% yield) of 1phenyl-1-mcthyl-1-hydroxy- 4-( l-pipcridyl)-2-butanonchydrochloride, M. P. 151 C.

Example 13],I (liphenyl-4-dietlzylamino-Z-batanone hydrochloride-Thiscompound was prepared by following a procedure similar to that outlinedin Example 3 and using a,a-diphenylacetone (21 grams, 0.10 mole),diethylamine hydrochloride (12 grams, 0.11 mole), paraformaldehyde (3.3grams, 0.11 mole) and 1 ml. of 7 N alcoholic hydrogen chloride. Afterheating the reaction mixture on a steam bath for one and one-half hoursthe solid prod not was crystallized from alcohol, then from acetone andfinally from isopropyl alcohol. There was obtained 14 grams (37% yield)of white needles, 1,1-diphenyl-4-diethylamino-Z-butanone hydrochloride,M. P. 144-145 C.

Example I4-J,J-cliplzen3, l-4-(1-piperidyl)-2-butan0nehydrochl0ride.--ot,ct-Diphenylacetone (13.1 grams, 0.0675 mole) wasmelted on a steam bath. iiperidinc hydrochloride (12 grams, 0.1 mole),paraforinaldehyde (3 grams, 0.1 mole) and 12 drops of 7 N alcoholichydrogen chloride was added. The mixture was heated on a steam bath withoccasional shaking for 20 minutes. The mix-o ture solidified to a massthat was quite insoluble in water. The solidl,l-diphenyl-4-(lpiperidyl)-2butanone hydrochloride with trituratetlwith two 30 ml. poo tions of 1:5 hydrochloric acid and then with 30 ofacetone and dried in air at 50. After crystallization from absolutealcohol (U. S. P.) it incited at 199-200 (10 grams, 43.5% yield).

Example 15-1,1 diphenyl-l-metlzyZ-4-dlmezhylamin0- Z-batanonelzydrchloride.3,3 diphenyl 2 butanone (13.6 grams, 0.06 mole),dimethylamine hydrochloride (4.9 grams, 0.06 mole) par iformaldehyde(2.0 grams, 0.066 mole), and 25 drops of 7 N alcoholic hydrogen chloridewere heated with occasional shaking on a steam bath for 3% hours. Thesolid that formed on cooling was triturated with 30 ml. of acetone,collected by filtration, and washed with acetone. The solid Weighed 9grams and melted at 8-161". After one crystallization from isopropylalcohol, there was obtained 7 grams (37%) ofl,l-phenyl-l-methyl-4-dimetbylamino-Z-butanone hydrochloride, M. P.165-166.

Example 16-4,l-rliphenyl-I-ethyl-4-tlimethylamin0-2- batanonehydrochloride.-Following the procedure outlined in Example 3,1,l-diphenyl-1-ethyl-2-propanone (11.9 grams, 0.05 mole), dimethylaminehydrochloride (4.5 grams, 0.055 mole), paraformaldehyde (1.7 grams,0.055 mole), and 1 ml. of 1 N alcoholic hydrogen chloride were heatedWith stirring on a steam bath for 26 hours. The solid which formed oncooling was triturated with ether and crystallized four times fromacetone. There was obtained 5.2 grams (31%) of1,1-diphenyl-lethyl'4-dimethylarnino-Z-butanone hydrochloride, M. P.152-153".

Example 17-1,] dipllenyl-l-allyl-4-a'imethylamino-Z- bazanonelzydr0chl0ricle.Using the procedure outlined in example 3 and 0.06 molequantities of 1,1-diphenyl- 1-a1lyl-2-propanone, paraformaldehyde, anddimethylamine hydrochloride, after successive recrystallizations of theproduct from ethyl acetate, benzene, and acetone there was obtained 1,1diphenyl-l-allyl 4 dimethylamino-Z- butanone hydrochloride, M. P.134135.

Example 18-] phenyl-J ,1 -di-n-pr0pyl 4 dimethylamino-Z-bmanonehyclrochloride.Using the procedure outlined in Example 3 and similarmolar quantities of u 3-plienyl-3-n-propyl-2-hexanone, paraformaldehyde,and dimethylamine hydrochloride, there was obtained 1-phenyl-1,ldi-n-propyl 4 dimethylamino-Z-butanone hydrochloride.

Example 19-] phenyl-l,1-rliallyl-4-dimethylamino-2- bataizonehydrochloride-Using the procedure outlined in Example 3 and similarquantities of 3-phenyl-3-a1lyl-5- hexen-2-one, paraformaldehyde anddimethylamine hydrochloride, there was obtainedl-phenyl-l,1-dia1lyl-4dimethylamino-Z-butanone hydrochloride.

Example 20-1-(m,p-dimethoxyplzenyl)l-npr0pyl-4- dimetlzylamino-Lbatanonehydrochloride-Using the procedure outlined in Example 3 and similarmolar quantities of 3-(m,p-dimethoxyphenyl)-2-hexanone,paraformaldehyde, and dimethylamine hydrochloride, there was ob tained 1(m,p-di1nethoxyphenyl)-1-n-propyl-4-dimethylamino-Z-butanonehydrochloride.

Example 21-1-(p-chlorophenyl)1-propyl-4-dlmethylamino-Z-butanonehydrochloride.Using the procedure outlined in Example 3 and similarmolar quantities of 3-(p-chlorophenyl)-2hexanone, paraformaldehyde, anddimethylamine, there was obtainedl-(p-chlorophenyU-lpropyl-4-dimethylamino-2-butanone hydrochloride.

Example 221 (1 piperl'dyl)-4(p-t0lyl)-4-phenyl3- batanonehydroclzloride.p-Tolyl-phenylacetone (22.4 grams, 0.1 mole) [preparedfrom phenylacetone and toluene in the manner described for thepreparation of diphenylacetone from phenylacetone and benzene (OrganicSynthesis 29, 38, (1949) )1, paraformaldehyde (3.3 grams, 0.11 mole),piperidine hydrochloride (12.2 grams, 0.1 mole) and concentratedhydrochloric acid (0.25 ml.) were mixed and heated with vigorousmechanical stirring on a steam bath for one hour. The solidcake thusproduced was crystallized from isopropyl alcohol yielding 1-(1-piperidyl) -4-(p-tolyl) -4-phenyl-3-butanone hydrochloride, M. l".181.2182.5 C.

Example 23J-(I piperidyl) 4 (p-ethylphenyl)-4-- phenyl-3-butart0nelzydrochloride.--By replacing the ptolylphenylacetone by anequimolecular quantity of pethylphenyl-phenylacetone (prepared fromphenylacetone and phenylethane in the manner described in OrganicSynthesis 29, 38 (1949), for the preparation of diphenylacetone) andfollowing substantially the same procedure described in Example 22,there is obtained l-(l-piperidyl) 4 (pethylphenyl)-4-phenyl-3-butanonehydrochloride.

Example 24-] (1 piperidyl)-4-(p-amylphenyl)-4- phenyl-3-butanonehydr0chloride.By replacing the ptolyl-phenylacetone by an equimolecularquantity of pamylphenyl-phenylacetone (prepared from phenylacetone andphenylpentane in the manner described in Organic Synthesis, 29, 38(1949) for the preparation of diphenylacetone) and followingsubstantially the same procedure described in Example 22, there isobtained l-(l-piperidyl) 4 (p amylphenyl)-4-phenyl-3-butanonehydrochioride.

Example 25-5-methyl 4 (p-bat0xyphenyl)-l-(I-piperidyUfi-lzexanonhydr0chl0rizle.-The heretofore unknown p-butoxyphenylacetone first wasprepared from pbutoxybenzaldehyde (136 grams, 0.765 mole) andnitroethane grams, 0.85 mole) in substantially the same manner describedin the Journal of Organic Chemistry 12, 501 (1947). This compound grams,0.365 mole) was isopropylated by reaction with isopropyl iodide (62grams, 0.365 mole) in the presence of potassium tertiary butoxide (0.365mole) in the usual manner, [Journal of the American Chemical Society 75,1072 (1953)], to obtain 1-(pbutoxyphenyl)-l-isopropylacetone. The lattercompound (12.4 grams, 0.05 mole), para'forinaldehyde (3.0 grams,

.1 mole), piperidine hydrochloride (6.5 grams, 0.054 mole) and a fewdrops of alcoholic hydrogen chloride were heated with vigorousmechanical stirring on a steam bath for one hour. The solid cake thusobtained was crystallized from acetone and from isopropyl alcoholyielding 5-methyl-4-(p-butoxyphenyl)-l-(lpiperidyl)-3- hexanonehydrochloride, M. P. 177-178 C.

Example 26-5 methyl 4 (m,p dibatoxyphenyl)- I (1 piperz'dyl) 3 hexanonehydrochloride-By replacing the p-butoxyphenylacetone by an equimolecularquantity of m,p-dibutoxyphenylacetone [prepared fromm,p-dibutoxybenzaldehyde and nitroethane as described in the Journal ofOrganic Chemistry 12, 501 (1947)], and following the same proceduredescribed in Example 25, there is obtained5-methyl-4-(m,p-dibutoxyphenyl)- 1-(1-piperidyl)-3-hexanonehydrochloride.

Example 27] (1 piperidyl) 4 (p-methoxyphenyl) 5 methyl 3 hexanonehydrochl0ria'e.-p-Methoxyphenylacetone (0.365 mole) was isopropylated bythe same process described in Example 25 to obtain 1-p-methoxyphenyl-l-isopropylacetone (B. P. -102 C. at 2 mm. pressure).The latter compound (10.3 grams, 0.05 mole), piperidine hydrochloride(6.5 grams, 0.054 mole), paraformaldehyde (3.0 grams, 0.1 mole) andalcoholic hydrogen chloride (0.25 ml.) were mixed and heated withvigorous mechanical stirring for one hour. The product,1-(l-piperidyl)-4-(p-methoxyphenyl)-5- methyl-3-hexanone hydrochloride,melted at 188-190 C. after crystallizing from isopropyl alcohol.

Example 28-] (1 piperidyl) 4 (m-melhoxyphenyl) 5 methyl 3 lzexanonehydrochloride-By replacing the p-methoxyphenylacetone by anequimolecular quantity of m-meti1oxyphenylacetone and followingsubstantially the same procedure described in Example 27, there wasobtained l-(l-piperidyl)-4-(m-methoxyphenyl)-5-methyl-3-hexanonehydrochloride, M. P. 151-152 C Example 29] (J piperidyl) 4 (phydroxyphem yl) 5 methyl 3 hexanone lzydr0chl0ride.--By replacing the1-( p-methoxyphenyl) acetone by an equimd lecular quantity of1-(p-hydroxyphenyl)acetone and following substantially the sameprocedure described in Example 27, there was obtained1-(1-piperidyl)-4-(p-hydroxyphenyl)-5-methyl-3-hexanone hydrochloride.

Example 30--] (p bromophenyl) 1- propyl 4- dimeflzylamino 2 butananehydrochl0ride.-Using the ass-races 7 procedure outlined in Example 3 andsimilar molar quan titles of 3-(p-bromophenyl)-2hexanone,paraformaldehyde and dimethylamine, there is obtained l-(p-bromophenyl)1 propyl 4 dimethylamino 2 butanone hydrochloride.

Example 3I-I phenyl 1 cyclohexyl 4 dimcthyL amino 2 butanonehydrochl0ride.Cyclohexylphcnyl acetone (11.2 grams, 0.052 mole),paraformaldehyde (4 grams, 0.13 mole), dimethylamine hydrochloride (4.2grams, 0.052 mole) were mixed and /2 ml. of 6 N alcoholic hydrogenchloride was added. The mixture was stirred and heated on a steam bathfor three hours at which time it had become a waxy solid. The solid wasremoved from the reaction flask, triturated with 100 cc. of boilingabsolute ether, and the solid was collected by filtration. The crudeproduct, after drying in air at 50-60 for 24 hours, weighed 12.4 grams.After two recrystallizations from acetone, there was obtained 3.4 gramsof 1-phenyl-l-cyclohexyl-4-dimethylamino-Z-butanone hydrochloride, M. P.169l70 C.

Example 32] (p chlorophenyl) 1 isopropyl 4- (1 pipe-tidy!) 2 butzmonehydrochloride.-Using the procedure outlined in Example 3 and similarmolar quantities of 3-(p-chlorophenyl)-4-methyl-2-pentanone, piperidinehydrochloride, and paraformaldehyde there was obtained 1 (pchlorophenyl) 1 isopropyl 4 (1- piperidyl)-2-butanone hydrochloride.

The foregoing examples are illustrative of the procedures and techniquesused to prepare the aminoketone of this invention such as:

1 phenyl 1 methyl 4 dimethylamino 2 butanone hydrochloride 1 phenyl 1methyl 4 (1 piperidyl) 2 butanone hydrochloride 1 phenyl 1 ethyl 4dimethylamino 2 butanone hydrochloride 1 phenyl 1 ethyl 4 (4morpholinyl) 2 butanone hydrochloride 1 phenyl l ethyl 4 (l piperidyl) 2butanone hydrochloride 1 phenyl 1 isopropyl 4 dimethylamino 2 butanonehydrochloride 1 phenyl l isopropyl 4 (1 piperidyl) 2 butanonehydrochloride 1 phenyl 1 propyl 4 (4 morpholinyl) 2 butanonehydrochloride 1 phenyl 1 allyl 4 dimethylamino 2 butanone hydrochloride1 phenyl 1 n propyl 4 dirncthylamino 2 butancne hydrochloride 1 phenyl 1n propyl 4 (l piperidyl) 2 butanone hydrochloride 1 phenyl 1 allyl 4 (lpiperidyl) 2 butanone hydrochloride 1 phenyl 1 n butyl 4 dirnethylamino2 butanone hydrochloride 1 phenyl 1 lauryl -4 dimethylarnino 2 butanonchydrochloride 1 phenyl 1 bcnzyl 4 dimcthylantino 2 butanonehydrochloride 1 phenyl 1 benzyl 4 (l piperidyl) 2 butanone hydrochloride1,1 diphenyl 4 dimethylamino 2 butanone hydrochloride 1,1 diphenyl 4diethylamino 2 butanone hydrochloride 1,1 diphenyl 4 (l piperidyl) 2butanone hydrochloride 1,1 diphenyl 1 methyl 4 dirncthylarnino 2butanone hydrochloride 1,1 diphenyl l ethyl 4 dimethylamino 2 butanonehydrochloride 1,1 diphenyl 1 allyl 4 dimethylamino 2 butanonehydrochloride 1,1 diphenyl 1 11 propyl 4 dimethylamino 2 butanonehydrochloride 1 phenyl 1,1 diallyl 4 dirnethylamino 2 butanonehydrochloride 1 phenyl l hydroxy l methyl 4 dimethylamino- Z-bntanonehydrochloride 1 phenyl 1 hydroxy 1 methyl 4- (1 piperidyD- Z-butanonehydrochloride 1 (p chlorcphenyl) 1 n propyl 4 dimethylamino- Z-butanonehydrochloride 1 (o crorncphenyD l allyl 4 (l piperidyl)-2- butanonehydrochloride 1 (o chlorophenyl) 1 (p bromophenyl) 4diethylamino-Z-butanone hydrochloride 1 These aminolretones, of course,are obtained by startwith the appropriate ketone A,.-C(R)(R)COCH amreacting it with equimolecular amounts of paraformaldehyde and theappropriate amine, HNX, according to the process described in any one ofthe preceding examples, in which A,., R, R and NX have the meaningsheretofore assigned.

it will be realized that the radicals (represented by R, R, A and NX inthe general formula) occurring in the foregoing compounds can bereplaced by the other radicals represented by a particular symbol toyield a variety of compounds other than those specifically enumeratedabove and it is intended that these be included within the presentdisclosure.

Example 331,1 diphenyl 4 (1 piperidyl) 2- butanone.1,l diphenyl 4 (lpiperidyl) 2 butano-ne hydrochloride (34.6 grams, 0.1 mole) (obtained asin Example 14) was dissolved in 200 ml. of water. This solution was madebasic with 20% sodium hydroxide solution. The free amine was taken up in150 ml. of ether. This ether solution was washed with two 50 ml.portions of water and dried over potassium carbonate. The potassiumcarbonate was removed by iiltration and the other by evaporation. Thecrude product was recrystallized from petroleum other. There wasobtained l,l--cliphenyl-4-( l-piperidyl 2-butanone.

The above outlined procedure for obtaining the free amine from thehydrochloride is applicable to any of the salts of the compounds of theinvention. Of course, in those instances in which the free amine isliquid rather than solid, it is conveniently isolated from the ethersolution (from which the drying agent, potassium carbonate, has beenremoved) by simple evaporation of the ether.

Other examples of the isolation of the free amines of the compounds ofthis invention are not included because to do so would be repetitious asthe above outlined procedures are applicable to any of the compounds ofthis invention.

it is to be realized that the aminoketones of this invention are morestable in the form of their salts than as the free amines and they arecustomarily utilized in the form of their salts. Any nontoxic salt canbe prepared and are envisaged within the scope of this invert-- tion.Particularly suitable salts are those which are nontoxic and watersoluble, for example salts prepared from inorganic acids and organicacids such as, for example, hydrochloric acid, hydrobrornic acid,sulfuric acid, glycoli-c acid, tartaric acid and p-toluenesulfonic acidto mention a few illustrative types. When the aminoltetone is producedin the form of a salt with any given acid, it is readily converted tothe salt of some other acid by treatment with alkali to liberate thefree base (as illustrated by Example 33 above) and subsequentneutralization with the desired acid. After the free base is prepared,it can, of course, be converted to the salt of any desired acid bysimple neutralization. The conversion or" the salt of the aminoketonewith one acid to the salt of another acid, or to the free base, or theneutralization of the free base to form salts, involves procedures whichare well known to those skilled in the art. The

following example illustrates the neutralization of the base prepared bythe process outlined in Example 33 with p-toluenesulfonic acid. As thesame neutralization procedure can be employed in making any of the momtoxic, water soluble salts, such as the hydrobromide, sulfate,glycolate" and tartrates, other examples of the preparation of thesesalts are not included.

Example 34-],1-diphenyl 4-(1-piperidyl)-2-butan0nep-tluenesulf0nate.1,1-diphenyl 4 (1-piperidyl)-2- butanone (0.1 mole)obtained as described in Example 31, was added to an aqueous solutioncontaining an equirnolecular quantity of p-toluenesulfonic acid. Thebase dissolved forming an aqueous solution of the ptoluenesulfonate saltof 1,1-dipheny1-4-(1-piperidyl)-2- butanone.

The foregoing examples are illustrative but not restrictive of the scopeof this invention.

What is claimed is:

1. A compound chosen from the class consisting of compounds of theformula in which Y is selected from the group consisting of hydrogen,hydroxy, lower alkyl, chlorine, bromine and References Cited in the fileof this patent UNITED STATES PATENTS 2,550,745 Wilder et al. May 1, 1951FOREIGN PATENTS 372,212 France Mar. 28, 1907

1. A COMPOUND CHOSEN FROM THE CLASS CONSISTING OF COMPOUNDS OF THEFORMULA